Down syndrome’s lessons

LEROY GIGLI noticed a change in his brother Dennis a few years ago. “All of a sudden he began to forget things ... where he’d put his wallet, his watch, etc.,” Leroy says.

Dennis, in his mid-50s at the time, was much younger than most people who come down with Alzheimer’s disease. But Leroy knew his brother had an added risk factor. Dennis has Down syndrome, a genetic disorder that affects one in 800 people at birth, causing mental retardation and other health problems, including a strong tendency to develop Alzheimer’s at an early age.

Dennis is now part of a clinical trial at UC Irvine aimed at slowing the ravages of Alzheimer’s. If effective, it could prove to also be a therapy to many in the general population.

It would be just one of several medical lessons that this genetic disorder can teach us. People with Down syndrome aren’t just more prone to get Alzheimer’s. They’re also less likely to get many kinds of cancer, and some evidence suggests they’re less prone to certain risk factors for heart disease. Understanding why the syndrome protects against some disorders and makes people more prone to others could point the way to new therapies for Down patients -- and everyone else.

“What we learn here might help the other 799 of 800,” says Dr. Julie Korenberg, who studies Down syndrome at Cedars-Sinai Medical Center and UCLA.

Down syndrome, the most common genetic cause of mental retardation, results from a fundamental mistake. Every cell in the body normally has two copies of each chromosome, the long strands of DNA that carry genetic instructions. But people with Down syndrome have a third copy of chromosome 21. That causes mild to moderate mental retardation, characteristic facial features and health problems that can include heart defects and difficulty fighting infections.

Studies have found that when it comes to solid tumors -- such as breast, colon and other common types of cancer -- those with Down syndrome “are the most protected of all humans,” says Dr. Judah Folkman, director of the vascular biology program at Children’s Hospital Boston. One large, 2002 study found that such cancers occurred less than 10% as often as expected in a group of nearly 18,000 Down syndrome individuals.

Folkman suspects that a naturally occurring protein called endostatin is largely responsible for the protection. His research, with colleagues, in the 1990s revealed that endostatin stunts the growth of tumors by impeding their blood supply. In 2001, researchers reported that people with Down syndrome have unusually high levels of endostatin in their bloodstreams, probably because the extra chromosome 21 gives them an extra gene involved in making endostatin.

Last year, a team led by Harvard biochemist Raghu Kalluri reported that tumors grew three times slower than usual in mice engineered to have endostatin levels similar to those found with Down syndrome.

Roger Reeves, a researcher at Johns Hopkins Medical School in Baltimore, thinks that other genes on chromosome 21 also contribute to the protective effect against cancer. Finding them could lead to cancer treatments -- perhaps drugs that can activate protective genes in people who don’t have Down syndrome.

Extra endostatin may even have benefits that extend beyond cancer protection. Recent mouse studies suggest the compound may interfere with atherosclerosis, the buildup of fatty plaques on blood vessel walls that can contribute to heart attack and stroke. And other studies have hinted that people with Down syndrome are less prone to high blood pressure.

To find out why, Korenberg is planning a study that will use imaging and biochemical tests to assess the cardiovascular health of people with Down syndrome. By combining those findings with genetic information about the participants, Korenberg hopes to identify genes related to heart health.

In the case of Alzheimer’s, autopsy studies have found the brain abnormalities associated with the disease in 100% of Down syndrome individuals older than 40 years. “Dementia occurs earlier and seems to run a faster course in people with Down syndrome,” says Dr. Ira Lott, director of pediatric neurology at UC Irvine.

Although nobody knows why that is, Lott suspects that part of the problem may be that people with Down syndrome are more sensitive to oxidative stress, a nasty type of chemical reaction that kills brain cells prematurely. Lott thinks it may be possible to counteract this process with a cocktail of antioxidants: vitamins C and E and a compound called alpha lipoic acid. He’s currently testing this idea in a clinical trial with 60 Down syndrome patients, including Dennis Gigli.

Dennis takes pills twice a day and has a neurological work-up every six months. He has been in the trial for a year and a half. His brother, Leroy, has realistic expectations: He knows that no treatment is likely to reverse the cognitive decline Dennis has already experienced.

“My hope is that it will smooth things so there’s not a drop off a cliff,” Leroy says. “We live day by day and see how things go.”

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A longer life span

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The life expectancy for people with Down syndrome is now in the mid-50s, and many live into their 60s and 70s. But that hasn’t always been the case. In 1929, the life expectancy was just nine years, and as recently as 1983 it was only 25. A major reason for the improvement is reconstructive heart surgery done shortly after birth, says Roger Reeves, a Down syndrome researcher at Johns Hopkins School of Medicine in Baltimore. About half of people with Down syndrome are born with heart defects, Reeves says, and about one in five have defects serious enough to require surgery.

For more information about Down syndrome, go to: www.nlm.nih.gov/medlineplus/downsyndrome.html